Melatonin — A Promising Candidate for Prevention and Treatment of COVID-19

Figure 1.  I-MASK+ (Prophylaxis & Early Outpatient Treatment Protocol for Covid-19)

In Figure 1, it shows the prophylaxis protocol proposed by FLCCC Alliance.^[1] And, the below items on the proposed list:

• Vitamin D3
• Vitamin C
• Quercetin
• Zinc
• Melatonin

are added as immune boosters for fighting Covid-19 virus.

In this article, we will discuss what melatonin is.

Melatonin — A promising treatment option for COVID-19

Melatonin, a hormone secreted by the pineal gland that regulates the sleep-wake cycle and is commonly used as an over-the-counter sleep aid.  It has wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound.

Based on multiple studies, melatonin is believed to be a promising candidate for prevention and treatment of Covid-19:

• University of Toronto^[2]
• Based on scientists' review, they discuss evidence implying that melatonin
• Prevents SARS-of CoV-2 infection
• Is suitable as an effective anti-inflammatory/immunoregulatory/antioxidant agent
• Counteracts chronodisruption
• Combats several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease
• Exerts a neuroprotective effect in acutely and chronically affected SARS-CoV-2 patients
• Can be an adjuvant to potentiate anti-SARS-CoV-2 vaccines. 
• Lerner Research Institute^[3]
• According to the findings published on 11/06/2020, a novel artificial intelligence platform developed by Lerner Research Institute researchers to identify possible drugs for COVID-19 repurposing has revealed melatonin as a promising candidate.
• Cleveland Clinic^[4]
• Analysis of patient data from Cleveland Clinic’s COVID-19 registry revealed that melatonin usage was associated with a nearly 30% reduced likelihood of testing positive for SARS-CoV-2 after adjusting for age, race, smoking history and various disease comorbidities. 
• Notably, the reduced likelihood of testing positive for the virus increased from 30 to 52 percent for African Americans when adjusted for the same variables.

Conclusion

CD147 is a glycoprotein that is responsible for the cytokine storm in the lungs through the mediation of viral invasion. Melatonin use previously was shown to reduce cardiac damage by blocking the CD147 activity. Hence, melatonin, a safe drug, may prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients. 

In [11], the authors concluded that the use of melatonin, which is reduced in the elderly and immune-compromised patients, should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effect.  

PAK1 is considered as a pathogenic enzyme and its unusual activation could be responsible for a broad range of pathologic conditions such as aging, inflammation, malaria, cancers immunopathology, viral infections, etc.^[8]  

Interestingly, melatonin exerts a spectrum of important anti-PAK1 properties in some abnormal conditions such as sleep disturbance, immune system effectiveness reduction, infectious disorders, inflammation, cancer, painful conditions, etc.^[6]Although it is not scientifically confirmed as yet, PAK1-inhibitors (incl. melatonin) could theoretically exert as potential agents for the management of a recent outbreak of COVID-19 infection. 

Indeed, Russel Reiter, a pioneer in melatonin research, has recently emphasized that melatonin may be incorporated into the treatment of COVID-19 as an alternative or adjuvant.^[6]

References

1. FLCCC Alliance (Front Line Covid-19 Critical Care Alliance)
2. Cardinali, D., Brown, G., and Pandi-Peruman, S. (2020). Can Melatonin Be a Potential “Silver Bullet” in Treating COVID-19 Patients? Diseases.
3. A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19
4. Melatonin a Promising Candidate for Prevention and Treatment of COVID-19
5. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings
6. Maruta H., He H. PAK1-blockers: potential therapeutics against COVID-19. Med. Drug Discov. 2020
7. Melatonin: Breakthrough Discoveries That Can Help You Combat Aging, Boost Your Immune System, Reduce Your Risk of Cancer and Heart Disease, Get a Better Night's Sleep Paperback – July 1, 1996
8. Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1‐dependent diseases and longevity. Phytother. Res. 2014;28(5):656–672.
9. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings
10. Öztürk G, Akbulut KG, Güney Ş. Turk J Med Sci. 2020 Oct 22; 50(6):1504-1512. Epub 2020 Oct 22.
11. Sehirli AO, Sayiner S, Serakinci N. Mol Biol Rep. 2020 Oct; 47(10):8229-8233. Epub 2020 Sep 12.

Top Zinc-Rich Foods For Better Immunity

Figure 1.  I-MASK+ (Prophylaxis & Early Outpatient Treatment Protocol for Covid-19)

In Figure 1, it shows the prophylaxis protocol proposed by FLCCC Alliance.^[1] And, the below items on the proposed list:

• Vitamin D3
• Vitamin C
• Quercetin
• Zinc
• Melatonin

are added to boost your immunity to fight Covid-19 virus.

In this article, we will discuss the best foods that are high in zinc.

Best Foods for Zinc

Zinc is found in cells throughout the body. It helps the immune system fight off invading bacteria and viruses. The body also needs zinc to make proteins and DNA, the genetic material in all cells. During pregnancy, infancy, and childhood, the body needs zinc to grow and develop properly.

The following foods are good sources for your daily zinc intake:^[3]

• Meat
• Meat is an excellent source of zinc.
• Shellfish
• Shellfish are healthy, low-calorie sources of zinc.
• Oysters contain particularly high amounts while other types of shellfish contain less zinc than oysters but are still good sources.
• Legumes
• Legumes like chickpeas, lentils and beans all contain substantial amounts of zinc.
• Seeds
• Hemp seeds contain particularly high amounts and other seeds (incl. squash, pumpkin and sesame seeds) also contain significant amounts of zinc 
• Nuts
• Eating nuts such as pine nuts, peanuts, cashews and almonds can boost your intake of zinc.
• Dairy
• Dairy foods like cheese and milk provide a host of nutrients, including zinc.
• Eggs
• Eggs contain a moderate amount of zinc and can help you meet your daily target.
• Whole grains
• Whole grains like wheat, quinoa, rice and oats contain some zinc.
• Some vegetables
• In general, fruits and vegetables are poor sources of zinc.  However, some vegetables contain reasonable amounts and eating a diet rich in vegetables has been linked to a reduced risk of chronic diseases like heart disease and cancer:
• Potatoes (both regular and sweet varieties), green beans and kale^[4]
• Dark chocolates 
• Perhaps surprisingly, dark chocolate contains reasonable amounts of zinc.

References

1. FLCCC Alliance (Front Line Covid-19 Critical Care Alliance)
2. Zinc Consumer Information (NIH)
3. The 10 Best Foods That Are High in Zinc
4. NutritionData 
5. Ivermectin & Carrageenan Study Shows Positive Results Targeting COVID-19
6. Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling 

Immunosenescence — Weaker Immune System of the Elderly Explained

Figure 1.  Diversity and clonal selection in the human T-cell receptor repertoire^[1] 

Key Points

1. T-Cell Receptor Diversity:

• As we age, T-cell receptor diversity declines due to shrinking thymus function.
• Thymus involution (thymus shrinkage) leads to fewer new T cells.

2. Immunosenescence:

• Immunosenescence refers to the age-related weakening of the immune system.
• It includes:
• Accumulation of dysfunctional memory T cells.
• Shortened telomeres (reduced cell lifespan).
• Impaired immune regulation.

3. Overall Changes:

• Aging results in:
• Weaker immune responses to new infections and vaccines.
• A shift toward inflammation.
• Increased susceptibility to autoimmune diseases, cancers, infections, and other age-related conditions.

4. Potential Solutions:

• Biomarkers (like CXCL9) can help identify individuals at risk for immunosenescence.
• Dietary interventions (such as prolonged fasting cycles) may alleviate immunosenescence.

5. COVID-19 and Aging:

• Older individuals are more vulnerable due to:
• Reduced T cell diversity and function.
• T cell senescence (contributing to ineffective immune response and inflammation).
• Lymphopenia (decreased lymphocyte count).

Understanding the aging-immune system connection is crucial for promoting healthy aging and addressing vulnerabilities.

TCR Diversity

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens (vs. self antigens), is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells (see Figure 1).

Immunosenescence

Immunosenescence is linked to:

• Functional decline associated with the passage of time 
• Antigen burden to which an individual has been exposed during lifetime

Some immunological parameters are commonly notably reduced in aged people. The principal immunosenescence hallmarks are represented by:^[2-5]

• Thymic involution
• The shrinking (involution) of the thymus with age
• T-cells are named for the thymus where T-lymphocytes migrate from the bone marrow to mature.
• Effects of the involution:
• Decreased new T cell generation and hematopoietic stem cell dysfunctions, decreased naïve and increased memory lymphocytes with accumulation of dysfunctional senescent cells with shortened telomeres.
• Defects in apoptotic cell death, mitochondrial function and stress responses
• Malfunctioning of immune regulatory cells

Loss of thymic function and T-cell receptor (TCR) diversity is thought to contribute to weaker immunosurveillance of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections. 

Senescent Immune System

A senescent immune system is characterized by continuous reshaping and shrinkage of the immune repertoire by persistent antigenic challenges. 

These changes lead to:

• A poor response to newly encountered microbial antigens, including vaccines
• A shift of the immune system towards an inflammatory, autoimmune, Th2 profile. 

This immune dysregulation provides the background for an increased susceptibility to 

• Autoimmune diseases
• Cancer
• Metabolic diseases
• Osteoporosis
• Neurological disorders
• Allergic inflammation 
• Infection

Accordingly, the severity of many infections is higher in the elderly compared to younger adults and infectious diseases are frequently associated with long-term complications and frailty.^[6–10] Reciprocally, an immune good function is tightly correlated to health status, as depicted in centenarian offspring.^{[11, 12]}

Biomarker for Immunosenescence

In Stanford's study on inflammatory clock (i.e., iAge), they have found a robust marker—chemokine CXCL9:

Which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule.

for chronic inflammation that could be potentially used to identify individuals with a decline in immunological function (immunosenescence), as well as those at risk for chronic disease and premature cardiovascular aging.

Can Prolonged Fasting Cycles Reverse Immunosenescence?

In one study,^[17] it indicates that cycles of an extreme dietary intervention represent a powerful mean to modulate key regulators of cellular protection and tissue regeneration but also provide a potential therapy to reverse or alleviate the immunosuppression or immunosenescence caused by chemotherapy treatment and aging, respectively, and possibly by a variety of diseases affecting the hematopoietic and immune systems and other systems and organs.

Roles of Aging Played in the Severity of COVID-19

Advanced age is a common co-morbidity for severity of disease during respiratory viral infections, and disease severity may be associated with altered T cell responses.^[13,14]

In summary, ageing can:^[15]

• Lag behind children in pre-activated antiviral innate immunity in the upper airways^[19]
• Affect T cell repertoire diversity
• For both CD4+ T cells and for CD8+ T cells.
• This age-related reduction in T cell clonal diversity is associated with impaired responses to viral infections such as influenza.
• Be associated with T cell senescence
• Advanced age can also be associated with T cell senescence, which perhaps contributes to ineffective responses to infections.
• Senescent T cells may also paradoxically be pro-inflammatory and therefore perhaps contribute to immunopathology.
• Be associated with lymphopenia
• Older patients experience more severe lymphopenia during COVID-19, although it is not clear whether ageing-associated lymphopenia is causal to disease severity or vice versa.

References

1. Diversity and clonal selection in the human T-cell repertoire 
2. Immune-inflammatory responses in the elderly: an update
3. Wistuba-Hamprecht K, Haehnel K, Janssen N, Demuth I, Pawelec G. Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the berlin aging study II. Immun Ageing. 2015;12:25. 6. 
4. Caruso C, Accardi G, Virruso C, Candore G. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing. 2013;10:20. 7. 
5. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15.
6.  Caruso C, Vasto S. Immunity and aging. In: Ratcliffe MJH, editor. Encyclopedia of Immunobiology, Vol. 5, pp. Oxford: Academic Press; 2016. p. 127–32.
7. Wistuba-Hamprecht K, Haehnel K, Janssen N, Demuth I, Pawelec G. Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the berlin aging study II. Immun Ageing. 2015;12:25. 
8. Caruso C, Accardi G, Virruso C, Candore G. Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? Immun Ageing. 2013;10:20. 
9. Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing. 2012;9:15. 
10. Caruso C, Candore G, Cigna D, DiLorenzo G, Sireci G, Dieli F, Salerno A. Cytokine production pathway in the elderly. Immunol Res. 1996;15:84–90
11.  Bucci L, Ostan R, Cevenini E, Pini E, Scurti M, Vitale G, Mari D, Caruso C, Sansoni P, Fanelli F, Pasquali R, Gueresi P, Franceschi C, Monti D. Centenarians’ offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. Aging (Albany NY). 2016;8:510–9. 
12. Pellicanò M, Buffa S, Goldeck D, Bulati M, Martorana A, Caruso C, ColonnaRomano G, Pawelec G. Evidence for less marked potential signs of T-cell immunosenescence in centenarian offspring than in the general agematched population. J Gerontol A Biol Sci Med Sci. 2014 May;69(5):495–504.
13. Lee, N., Shin, M. S. & Kang, I. T-cell biology in aging, with a focus on lung disease. J. Gerontol. A Biol. Sci. Med. Sci. 67, 254–263 (2012).
14. Goronzy, J. J. & Weyand, C. M. Successful and maladaptive T cell aging. Immunity 46, 364–378 (2017).
15. T cell responses in patients with COVID-19
16. An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans
17. Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression
18. Can Intermittent Fasting Reset Your Immune System?
19. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

Ivermectin & Carrageenan Study Shows Positive Results Targeting COVID-19

Figure 1.  I-MASK+ (Prophylaxis & Early Outpatient Treatment Protocol for Covid-19)

Headline News

FDA Drops Ivermectin Bombshell  (08/11/2023)

Doctors are free to prescribe ivermectin to treat COVID-19, a lawyer representing the U.S. Food and Drug Administration (FDA) said this week. 

Top Yale Doctor/Researcher: ‘Ivermectin works,’ including for long-haul COVID

Oxford University explores anti-parasitic drug ivermectin as COVID-19 treatment (06/23/2021)

In an open-label randomized clinical trial of high-risk patients with COVID-19 in Malaysia, a 5-day course of oral ivermectin administered during the first week of illness did not reduce the risk of developing severe disease compared with standard of care alone. (02/18/2022)

Based in the southern end of Greater Buenos Aires, Argentina, Eurnekian Public Hospital recently sponsored a clinical trial targeting COVID-19 called the IVERCAR study.^[2] The sponsor was joined by other local hospitals acting as trial site organizations. 

The study team recruited 1,195 health professionals of which 407 received no treatment and 788 self-administered ivermectin oral drops and an iota-carrageenan nasal spray five times per day over a 14 day period.

The Argentinian study team reported that the study data revealed that of the participants in the control group (e.g. not taking the study drug combination) 58% of the participants were infected with COVID-19 during the duration of the trial. The treatment group reported no contagions were recorded in the carrageenan and ivermectin arm, showcasing the compounds’ virucidal effects can potentially protect against COVID-19.^[1]

Figure 2.  Warning: Do not take Ivermectin for horses or cows only.

If you ever take it, should take it from your doctor and be monitored.

Highlights for ivermectin

1. Ivermectin oral tablet is available as a brand-name drug and a generic drug. Brand-name: Stromectol.
• Ivermectin also comes as a cream and a lotion you apply to your skin.
• Ivermectin oral tablet is used to treat parasitic infections of your intestinal tract, skin, and eyes.
• See Ivermectin information published on the Mayo Clinic here.  Note that when this article was written the link to the Mayo Clinic article existed.  But, later probably due to FDA's opposition of prescribing Ivermectin to COVID-19, it was removed.
2. Ivermectin is FDA-approved for use in animals for prevention of heartworm disease in some small animal species, and for treatment of certain internal and external parasites in various animal species. 
• FDA warns that  people should never take animal drugs, as the FDA has only evaluated their safety and effectiveness in the particular species for which they are labeled. Using these products in humans could cause serious harm. 
• Ivermectin should be prescribed by your doctor.
3. In [9], Pierre Kory et al. had reviewed the emerging evidence demonstrating the efficacy of Ivermectin in the prophylaxis and treatment of COVID-19
• Ivermectin is also used as one of the ingredients in the Prophylaxis & Early Outpatient Treatment Protocol for Covid-19 announced at the FLCCC Alliance Press Conference (see video 1)
• See FLCCC Alliance web site for more clinical studies

Figure 3.  Ivermectin was said to have high activity against Covid-19

Side Effects of Ivermectin

More common side effects

The side effects of this drug depend on the condition being treated.

The more common side effects of this drug when it’s used to treat intestinal infections include:

• tiredness
• loss of energy
• stomach pain
• loss of appetite
• nausea
• vomiting
• diarrhea
• dizziness
• sleepiness or drowsiness
• itchiness

The more common side effects of this drug when it’s used to treat skin and eye infections include:

• joint pain and swelling
• swollen and tender lymph nodes
• itching
• rash
• fever
• eye problems

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 911 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• Pain in your neck and back
• Serious eye problems. Symptoms can include:
• redness
• bleeding
• swelling
• pain
• loss of vision
• Shortness of breath
• Inability to control urination
• Inability to control bowel movements
• Trouble standing or walking
• Confusion
• Extreme tiredness
• Extreme drowsiness
• Seizures
• Coma
• Low blood pressure, especially when you get up after sitting or lying down. Symptoms can include:
• lightheadedness
• dizziness
• fainting
• Severe skin reactions. Symptoms can include:
• severe rash
• redness
• blistering skin
• peeling skin
• Liver damage. Symptoms can include:
• tiredness
• nausea
• vomiting
• loss of appetite
• pain on the right side of your stomach
• dark urine
• yellowing of your skin or the whites of your eyes

More about Ivermectin

Read [2] for more information regarding Ivermectin's other effects:

• Interaction with other medications
• Other warnings for people with
• Allergy 
• Certain health conditions
• Others 

Video 1.  Ivermectin Toxicity Reviewed (YouTube link)

Video 2.  William C. Campbell - Nobel Lecture: Ivermectin: A reflection on simplicity (YouTube link)

Video 3.  Home ivermectin based kits in India (YouTube link)

Video 4.  New Pfizer drug and ivermectin (YouTube link)

Highlights of Carrageenan 

1. Different forms of carrageenan have different uses and potential risks
2. Carrageenan is a common food additive extracted from red seaweed
• Manufacturers often use it as a thickening agent
3. FDA have approved the additive for use, but concerns about its safety remain
• Some scientists believe that carrageenan can cause inflammation, digestive problems, such as bloating and irritable bowel disease (IBD), and even colon cancer
• However, the validity of these claims is hotly debated because the only supporting evidence comes from studies in cells and animals
4. In IVERCAR study and Healthcare Technology Institute (HTI) study, both use carrageenan in their nasal spray as the prophylaxis and treatment of Covid-19
• To maintain the advantage of λcarrageenan’s intrinsic anti-viral capacity,^[12-14] HTI has formulated a composite mixture containing increasing amounts of gellan to λcarrageenan to allow for the optimization of its nasal therapy.
5. In a new clinical trial named "Iota-carrageenan Nasal Spray COVID-19 Prophylaxis for Healthcare Professionals (ICE-COVID)", it claims that:

SARS-CoV-2 is a positive-sense single-stranded enveloped RNA virus which transmits via droplets, aerosols and direct contact, to reach their target naso- and oropharyngeal epithelial cells through initial electrostatic interactions to cell surface heparan sulphate (HS) proteoglycans. Carrageenan mimics cell surface HS, thereby trapping the virus to allow mucociliary clearance and has demonstrated anti-viral activity in-vitro and in a number of common cold clinical trials when administered as a nasal spray.

Final Words

Consult with your physicians for the final decision of using this option for Covid-19 prevention or treatment.  This article presented here is just for your information only.  Note that COVID-19 is a serious disease and everyone, if infected by SARS-CoV-2, could have different outcome.

Reference

1. Argentina’s IVERCAR Ivermectin & Carrageenan Study Shows Positive Results Targeting COVID-19
2. USEFULNESS of Topic Ivermectin and Carrageenan to Prevent Contagion of Covid 19 (IVERCAR)
3. Ivermectin, oral tablet
4. Formulation of a composite nasal spray enabling enhanced surface coverage and prophylaxis of SARS-COV-2
5. Harden EA, Falshaw R, Carnachan SM, Kern ER, Prichard MN. Virucidal activity of polysaccharide extracts from four algal species against herpes simplex virus. Antiviral Res. 2009 Sep;83(3):282-9. doi: 10.1016/j.antiviral.2009.06.007. Epub 2009 Jul 1.
6. Carlucci MJ, Scolaro LA, Noseda MD, Cerezo AS, Damonte EB. Protective effect of a natural carrageenan on genital herpes simplex virus infection in mice. Antiviral Res. 2004 Nov;64(2):137-41.
7. Ashraf S, Prichard R. Ivermectin exhibits potent anti-mitotic activity. Vet Parasitol. 2016 Aug 15;226:1-4. doi: 10.1016/j.vetpar.2016.06.015. Epub 2016 Jun 11.
8. Is carrageenan safe to eat?
9. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
10. Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial
11. Iota-carrageenan Nasal Spray COVID-19 Prophylaxis for Healthcare Professionals (ICE-COVID)
12. Carrageenan is a potent inhibitor of papillomavirus infection
13. Iota-Carrageenan is a potent inhibitor of rhinovirus infection
14. Prevention of human enterovirus 71 infection by kappa carrageenan
15. FAQ: COVID-19 and Ivermectin Intended for Animals
16. Ivermectin (Oral Route) (Mayo Clinic)
17. FLCCC Alliance (Front Line Covid-19 Critical Care Alliance)
18. Top Yale Doctor/Researcher: ‘Ivermectin works,’ including for long-haul COVID
19. Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study
• Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month.
20. Dr. William Campbell 2015 Nobel Prize in Medicine for discovering an anti-parasitic drug (i.e., Ivermectin) that treats diseases caused by the roundworm
21. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines
• Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
22. Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial
• Based on the findings from the present study, a single weight-based dose (0.2 mg/kg) of ivermectin could improve important clinical symptoms in patients with COVID-19, such as dyspnea, cough, and lymphopenia. This drug was well tolerated, with a good tolerability profile and few adverse events with oral administration.
23. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial (published by THE LANCET)
• Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.
24. Favorable outcome on viral load and culture viability using Ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial
25. Effects of Ivermectin therapy on the sperm functions of Nigerian onchocerciasis patients
26. Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach
• Ivermectin was found to be an efficient inhibitor of Mpro, replicase and hTMPRSS2 and the study manifests a superior ground for the candidature of ivermectin to be an efficient anti-SARS-CoV-2 therapeutic option.
27. UTTAR PRADESH Going the last mile to stop COVID-19
28. Rapid initiation of nasal saline irrigation to reduce morbidity and mortality in COVID+ outpatients: a randomized clinical trial compared to a national dataset
• Participants were randomly assigned adding 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240ml of isotonic nasal irrigation twice daily for 14 days.
29. Interim analysis of an open-label randomized controlled trial evaluating nasal irrigations in non-hospitalized patients with coronavirus disease 2019
30. Iota-carrageenan neutralizes SARS-CoV-2 and inhibits viral replication in vitro

Hesperidin — a promising adjuvant treatment option against SARS-CoV-2 infection

Hesperidin is a bioflavonoid, a type of plant pigment with antioxidant and anti-inflammatory effects found primarily in citrus fruit (see Figure 1).  Oranges, grapefruit, lemon, and tangerines all contain hesperidin, which is also available in supplement form. Note that hesperidin is present in highest concentration in the peel.

Figure 1.  Citrus fruits

A Traditional Herbal Medicine

Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. The safety of hesperidin was confirmed by FASEB (Federation of American Societies of Experimental Biology) upon request of the FDA.

Cellular Entry of Covid-19

Cell entry of Covid-19 depends on two consecutive steps:

1. Binding of the viral spike (S-protein) to host cellular receptors 
2. Followed by priming of S-protein by cell proteases

Recently, researchers showed that COVID-19 uses the ACE-2 receptor for entry and the serine protease TMPRSS2 for priming of S-protein.^[4]

Figure 2.  Hesperidin role in prevention and treatment of COVID 19

Adjuvant treatment option against Covid-19

Host antiviral responses against COVID-19 infection depend on the activation of both the immune systems and cellular self-defense mechanisms. The occurrence of immune over-response or immune deficiency is responsible for the condition of infected Covid-19 patients becoming critical or severe.^[6]

Hesperidin has several pharmacological activities such as anti-atherogenic, antihyperlipidemic, antidiabetic, venotonic, cardioprotective, anti-inflammatory, and antihypertensive actions.  Available evidence supports the promising use of hesperidin in prevention and treatment of Covid-19.  For example, hesperidin can potentially (See Figure 2):^[1]

• Prevent the Covid-19 infection
• Based on virtual screening, hesperidin may disrupt the interaction of ACE2 with RBD of SARS-CoV-2 thus block its entry into the lung cells.^[5]
• Improve host cellular immunity against infection
• A recent study showed that the interferon-MAPK pathway played an important role in the COVID-19 immune response.^[6]
• Hesperidin by its activation to host immunity may help against COVID-19 viral replication and hence its progression which will improve the patient outcome (Figure 1).
• Hesperidin exhibited anti-viral activity against the influenza virus through a significant reduction of virus replication. 
• Treatment of infected cells with hesperidin enhanced cell-autonomous immunity via activation and upregulation of p38 and JNK expression which is essential for cell defense mechanisms against influenza virus.^[2]
• Control cytokine storm
• The anti-inflammatory activity of hesperidin was mainly attributed to its antioxidant defense mechanism and suppression of pro-inflammatory cytokine production.^[3]
• Prevent disease progression
• Activation of coagulation pathways following the immune response to COVID-19 infection promotes clot formation.
• A prophylactic dose of heparin (with low molecular weight, LMWH) is recommended for protection against venous thromboembolism in COVID-19 hospitalized patients.^[8]
• Co-administration of LMWH and Daflon 500 mg can significantly inhibit clot formation and prevent disease progression.^[9]

References

1. Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?
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